Processes for preparing different forms of (s)-(+)-clopidogrel bisulfate

ABSTRACT

The invention provides improved processes for the preparation of hydrated form of (S)-(+)-Clopidogrel bisulfate as well as improved processes for the preparation of form-I and form-II of (S)-(+)-Clopidogrel bisulfate.

FIELD OF INVENTION

The present invention relates to improved processes for the preparationof different forms of clopidogrel bisulfate. The present inventionparticularly describes improved processes for the preparation ofamorphous (S)-(+)-Clopidogrel bisulfate and Form I of(S)-(+)-Clopidogrel bisulfate. More particularly, in a preferredembodiment, the present invention discloses improved processes for thepreparation of amorphous form of (S)-(+)-Clopidogrel bisulfate ashydrates, solvates and various pharmaceutical compositions containingthe amorphous forms prepared according to the present invention.

In another preferred embodiment, this invention describes improvedprocesses for the preparation of Form I, Form II polymorphs ofS-(+)-Clopidogrel bisulfate and pharmaceutical compositions containingthem. (S)-(+)-Clopidogrel bisulfate an antiplatelet drug is currentlybeing marketed for the treatment of atherosclerosis, myocardialinfraction, strokes and vascular death. The present invention alsodescribes a method of treatment of such cardiovascular disorders usingthe different forms of Clopidogrel bisulfate or mixtures thereofprepared according to the present invention, and pharmaceuticalcompositions containing them. The present invention further relates tothe use of the different forms of (S)-(+)-Clopidogrel bisulfate preparedaccording to the processes disclosed herein and pharmaceuticalcompositions containing them for the treatment of cardiovasculardisorders.

BACKGROUND OF THE INVENTION

Clopidogrel bisulfate corresponds to the empirical formulaC₁₆H₁₆ClNO₂S.H₂SO₄. Chemically it is methyl(+)-(S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetatesulfate (1:1), having the following structural formula.

Clopidogrel is an inhibitor of platelet aggregation and is marketed asan antianginal agent, antiplatelet agent and is found to decrease morbidevents in people with established atherosclerotic cardiovascular diseaseand cerebrovascular diseases.

The therapeutic application of Clopidogrel as blood-platelet aggregationinhibiting agents and antithrombotic agent and its preparation isdisclosed in U.S. Pat. No. 4,529,596.

U.S. Pat. No. 4,847,265 describes the process for the preparation of thehydrogen sulfate salt of Clopidogrel.

Various other strategies to prepare Clopidogrel are disclosed in WO98/51681, WO 98/51682, WO 98/51689, WO 99/18110, U.S. Pat. No.5,036,156, U.S. Pat. No. 5,132,435, U.S. Pat. No. 5,139,170, U.S. Pat.No. 5,204,469 and U.S. Pat. No. 6,080,875.

U.S. Pat. No. 4,847,265 discloses that the dextrorotatory enantiomer offormula (I) of Clopidogrel has an excellent antiaggregant plateletactivity, whereas the corresponding levorotatory enantiomer is lesstolerated and is less active. U.S. Pat. No. 4,847,265 relates to thedextrorotatory enantiomer and its pharmaceutically acceptable salts withplatelet aggregation inhibiting activity.

Subsequently filed Patent Application WO 99/65915 (U.S. Pat. No.6,429,210) titled “Polymorphic Clopidogrel hydrogen sulfate form”, whichis herein incorporated by reference, discloses the existence of aspecific polymorphic Form II of the hydrogen sulfate of(S)-(+)-Clopidogrel (m.p.=176±3° C.). It is also disclosed in thispatent application that the earlier processes described in the U.S. Pat.No. 4,847,265 gives Form I (m.p. 184±3° C.). These two crystallinepolymorphic forms I and II differed in their stability, physicalproperties, spectral characteristics and their method of preparation.However, both the polymorphs have similar bioavailability, as shown intheir bioequivalence in healthy human volunteers.

Although, U.S. Pat. No. 4,847,265 reports the formation of(S)-(+)-Clopidogrel bisulfate salt with m.p. 184° C., it was disclosedas Form I only in patent application WO 99/65915. However, areproducible and consistent method for the preparation of Form I withchirally pure material (ee>99%) was in doubt since chiral purity of thematerial (Clopidogrel bisulfate) with m.p. 184±3° C., disclosed in U.S.Pat. No. 4,847,265 was not precisely known.

In fact, we have observed that formation of Form I of(S)-(+)-Clopidogrel bisulfate with chiral purity >99% e.e. isinconsistent and difficult to reproduce using the procedures reported inU.S. Pat. No. 4,847,265 and WO 99/65915 whereas the formation of Form IIis extremely facile and consistent with optically pure(S)-(+)-Clopidogrel free base.

We have earlier disclosed improved processes for the manufacture of(S)-(+)-Clopidogrel bisulfate & its intermediates [Indian PatentApplications 84/MUM/2001 (WO 02059128/U.S. Pat. No. 6,635,763), &335/MUM/2001] which are cited herein in their entirety as reference.

We have also disclosed hydrated form of amorphous Clopidogrel bisulfateas well as methanolates, ethanolates and containing different formstabilizers [Indian patent application 1154/MUM/2003 and 413/MUM/2003],which are also incorporated as reference.

Amorphous Clopidogrel bisulfate and other solvated forms (1-butanol,2-butanol, isopropanol, 1-propanol) as well mixtures of amorphous formwith Form I and Form II and processes for preparing them have beendisclosed in Teva's application no. WO 03/051362 A2, which is citedherein as reference. However, this application does not discloseamorphous Clopidogrel bisulfate hydrate.

Teva's application also discloses processes for preparing Form I andForm II of Clopidogrel bisulfate. The Form I is prepared by contactingthe amorphous form disclosed therein in ethers preferably diethyl etheror MTBE. These processes have the following disadvantages:

-   i. diethyl ether and MTBE are very volatile and inflammable hence    are hazardous to work with;-   ii. the process is difficult to be scaled up to plant scale;-   iii. problem of recovery of antisolvents further making the process    economically unfeasible.

We herein disclose improved processes for preparing amorphousClopidogrel bisulfate, amorphous Clopidogrel bisulfate hydrate,amorphous Clopidogrel bisulfate solvates, with high optical purity(ee>99%).

We also disclose improved processes for preparing Form I and Form II ofClopidogrel bisulfate. Also disclosed are amorphous Clopidogrelbisulfate, Form I and Form II of Clopidogrel bisulfate withcharacteristic impurity profile.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide an improvedprocesses for preparation of amorphous (S)-(+)-Clopidogrel bisulfate inhydrate form containing from about 1-4% water.

Yet another object of the present invention is to provide improvedprocesses for the preparation of amorphous Clopidogrel bisulfatesolvates.

A still further object of the present invention is to provide improvedprocesses for the preparation of Form I of Clopidogrel bisulfate.

A still further object of the present invention is to provide improvedprocesses for the preparation of Form II of Clopidogrel bisulfate.

As an embodiment of the present invention pharmaceutical compositionscontaining the various amorphous forms of Clopidogrel bisulfate, Form Iand Form II described herein and prepared according to the presentinvention are provided.

Also is provided a method of treatment and use of the various amorphousforms of Clopidogrel bisulfate, Form I and Form II described herein andprepared according to the present invention for the treatment ofcardiovascular disorders, comprising administering, for example, orallya composition of the invention in a therapeutically effective amount.

These processes are easy to scale up, commercially viable, safe, easy tohandle and provides operational simplicity.

DESCRIPTION OF INVENTION

The present invention discloses improved processes for the preparationof different forms of clopidogrel bisulfate.

The present invention provides improved processes for the preparation ofdifferent amorphous forms of Clopidogrel bisulfate as described elsewhere in the specification. The term “amorphous”, as used herein,relates to solid material which lacks a regular crystalline structure.In a powder X-ray diffractogram such material gives no good intensitypeaks. Whenever sulfuric acid is being used for preparing the bisulfatesalt as disclosed in the specification, it is used in the range of0.95-1.25 mole equivalent. The term Clopidogrel base, Clopidogrelbisulfate used in the specification means (S)-(+)-Clopidogrel base and(S)-(+)-Clopidogrel bisulfate respectively.

The various amorphous forms (hydrates, solvates, amorphous formcontaining form stabilizers) described in the specification can beprepared by any of the processes described below or used in combination.

-   i) clopidogrel base in suitable solvents is treated with dil. H₂SO₄,    the solvent is evaporated and amorphous form is precipitated by    addition of a suitable antisolvent(s). Suitable solvents can be    selected from methanol, ethanol, propanol, isopropanol, 1-butanol,    2-butanol, dichloromethane, dimethyl formamide, dimethyl acetamide,    1,4-dioxane, tetrahydrofuran and the like or mixtures thereof.    Suitable antisolvents may be selected from pentane, n-hexane,    heptane, cyclohexane, pet ethers and the like or mixtures thereof.-   ii) clopidogrel base in suitable solvents and water is treated with    concentrated H₂SO₄, the solvent is evaporated and amorphous form is    precipitated by addition of a suitable antisolvent(s). Suitable    solvents can be selected from methanol, ethanol, propanol,    isopropanol, 1-butanol, 2-butanol, dichloromethane, dimethyl    formamide, dimethyl acetamide, 1,4-dioxane, tetrahydrofuran and the    like or mixtures thereof. Suitable antisolvents may be to selected    from pentane, n-hexane, heptane, cyclohexane, pet ethers and the    like or mixtures thereof-   iii) clopidogrel bisulfate in dichloromethane-water is treated with    suitable bases, to obtain Clopidogrel base which is then treated    with dil. H₂SO₄ in suitable solvents, the solvent is evaporated and    the amorphous form is precipitated by addition of a suitable    antisolvent(s). Suitable bases can be selected from NaOH, KOH, LiOH,    NaHCO₃, Na₂CO₃, K₂CO₃ and the like. Suitable solvents can be    selected from methanol, ethanol, propanol, isopropanol, 1-butanol,    2-butanol, dichloromethane, dimethyl formamide, dimethyl acetamide,    1,4-dioxane, tetrahydrofuran and the like or mixtures thereof.    Suitable antisolvents may be selected pentane, n-hexane, heptane,    cyclohexane, pet ethers and the like or mixtures thereof-   iv) clopidogrel bisulfate in dichloromethane—water is treated with    suitable bases, to obtain Clopidogrel base which is then treated    with concentrated H₂SO₄ in a mixture of suitable solvents and water,    the solvent is evaporated and amorphous form precipitated by    addition of suitable antisolvent(s). Suitable bases can be selected    from NaOH, KOH, LiOH, NaHCO₃, Na₂CO₃, K₂CO₃, organic bases like    tertiary alkyl amines and the like. Suitable solvents can be    selected from methanol, ethanol, propanol, isopropanol, 1-butanol,    2-butanol, dichloromethane, dimethyl formamide, dimethyl acetamide,    1,4-dioxane, tetrahydrofuran and the like or mixtures thereof.    Suitable antisolvents may be selected pentane, n-hexane, heptane,    cyclohexane, pet ethers and the like or mixtures thereof-   v) (S)-(+) Clopidogrel camphor-sulfonate in suitable solvents like    ethyl acetate, dichloromethane, dichloroethane, chloroform and the    like and water is treated with a suitable base, to obtain    Clopidogrel base which is then treated with dil. H₂SO₄ in suitable    solvents. The solvent is evaporated and amorphous form is    precipitated by addition of suitable antisolvent(s). Suitable bases    can be selected from NaOH, KOH, LiOH, NaHCO₃, Na₂CO₃, K₂CO₃, organic    bases like tertiary alkyl amines and the like. Suitable solvents can    be selected from methanol, ethanol, propanol, isopropanol,    1-butanol, 2-butanol, dichloromethane, dimethyl formamide, dimethyl    acetamide, 1,4-dioxane, tetrahydrofuran and the like or mixtures    thereof. Suitable antisolvents may be selected from pentane,    n-hexane, heptane, cyclohexane, pet ethers and the like or mixtures    thereof.-   vi) (S)-(+) Clopidogrel camphor-sulfonate in suitable solvents like    ethyl acetate, dichloromethane, dichloroethane, chloroform and the    like and water is treated with a suitable base, to obtain    Clopidogrel base which is then treated with concentrated H₂SO₄ in a    mixture of suitable solvent(s) and water. The solvent is evaporated    and amorphous form precipitated by addition of suitable antisolvent.    Suitable bases can be selected from NaOH, KOH, LiOH, NaHCO₃, Na₂CO₃,    K₂CO₃, organic bases like tertiary alkyl amines and the like.    Suitable solvents can be selected from methanol, ethanol, propanol,    isopropanol, 1-butanol, 2-butanol, dichloromethane, dimethyl    formamide, dimethyl acetamide, 1,4-dioxane, tetrahydrofuran and    mixtures thereof. Suitable antisolvents may be selected from    pentane, n-hexane, heptane, cyclohexane, pet ethers and the like or    mixtures thereof.

Various polyethylene glycols (PEG) 200, 400, 800, 900, 1000, 1200, 2000and 4000 can also be used as amorphous form stabilizers in any of theprocesses described above.

Alternatively, the processes [(i)-(vi)] described above can be repeatedby using the Clopidogrel base, (S)-(+) Clopidogrel bisulfate and (S)-(+)Clopidogrel camphor-sulfonate prepared according to the improvedprocesses described by the applicant in WO 02059128/U.S. Pat. No.6,635,763.

The present invention also describes improved processes for thepreparation of Form I of Clopidogrel bisulfate from the differentamorphous forms prepared according to any of the processes of thepresent invention. The Form I is obtained by treating the aboveamorphous forms in a mixture of diethyl ether-heptane, diethylether-hexane, diethyl ether-pet ethers in various combination andproportion, with a view to enhance operational safety, scalability andsimplicity.

The Form I can also be prepared by any of the processes described beloweither alone or used in combination:

-   (i) clopidogrel base in suitable solvent(s) selected from C₆-C₁₂    alcohols is treated with dil. H₂SO₄, to obtain Form I of    (S)-(+)-Clopidogrel bisulfate. Suitable solvents can be selected    from C₆-C₁₂ alcohols which may be linear or branched, primary,    secondary or tertiary alcohols such as 1-hexanol, 2-hexanol,    3-hexanol, isohexanol, 1-heptanol, 2-heptanol, 3-heptanol,    4-heptanol, octanol, isooctanol, decanol, and the like or mixtures    thereof.-   (ii) clopidogrel base in suitable solvent(s) selected from C₆-C₁₂    alcohols and a trace of water is treated with concentrated H₂SO₄, to    obtain Form I of (S)-(+)-Clopidogrel bisulfate. Suitable solvents    may be selected from C₆-C₁₂ alcohols which may be linear or    branched, primary, secondary or tertiary alcohols such as hexanol,    2-hexanol, 3-hexanol, isohexanol, 1-heptanol, 2-heptanol,    3-heptanol, 4-heptanol, octanol, isooctanol, decanol, and the like    or mixtures thereof.-   (iii) clopidogrel bisulfate in any form including different    crystalline forms such as Forms II, III, IV, V, VI etc. or amorphous    form or in the form of oil is dissolved/contacted with suitable    solvent(s) selected from C₆-C₁₂ alcohols to obtain Form I of    (S)-(+)-Clopidogrel bisulfate. Suitable solvents can be selected    from C₆-C₁₂ alcohols which may be linear or branched, primary,    secondary or tertiary alcohols such as 1-hexanol, 2-hexanol,    3-hexanol, isohexanol, 1-heptanol, 2-heptanol, 3-heptanol,    4-heptanol, octanol, isooctanol, decanol, and the like or mixtures    thereof.-   (iv) clopidogrel bisulfate in any form including crystalline forms    II, III, IV, V, VI etc. or amorphous form or in the form of oil is    dissolved/contacted with suitable solvent(s) selected from C₆-C₁₂    alcohols and a trace of water, to obtain Form I of    (S)-(+)-Clopidogrel bisulfate. Suitable solvent(s) can be selected    from C₆-C₁₂ alcohols which may be linear or branched, primary,    secondary or tertiary alcohols such as 1-hexanol, 2-hexanol,    3-hexanol, isohexanol, 1-heptanol, 2-heptanol, 3-heptanol,    4-heptanol, octanol, isooctanol, decanol, and the like or mixtures    thereof.-   (v) (S)-(+) Clopidogrel camphor-sulfonate in suitable solvent(s)    like ethyl acetate, dichloromethane, dichloroethane, chloroform and    the like and water is treated with suitable base(s), to obtain    Clopidogrel base which is then treated with dil. H₂SO₄ in suitable    solvent(s), selected from C₆-C₁₂ alcohols to obtain Form I of    (S)-(+)-Clopidogrel bisulfate. Suitable bases can be selected from    NaOH, KOH, LiOH, NaHCO₃, Na₂CO₃, K₂CO₃, organic bases like tertiary    alkyl amines and the like. Suitable solvents can be selected from    C₆-C₁₂ alcohols which may be linear or branched, primary, secondary    or tertiary alcohols such as 1-hexanol, 2-hexanol, 3-hexanol,    isohexanol, 1-heptanol, 2-heptanol, 3-heptanol, 4-heptanol, octanol,    isooctanol, decanol, and the like or mixtures thereof-   (vi) clopidogrel camphor-sulfonate in suitable solvent(s) like ethyl    acetate, dichloromethane, dichloroethane, chloroform and the like    and water is treated with suitable base(s), to obtain Clopidogrel    base which is then treated with concentrated H₂SO₄ in suitable    solvent(s), selected from C₆-C₁₂ alcohols and a trace of water to    obtain Form I of (S)-(+)-Clopidogrel bisulfate. Suitable bases can    be selected from NaOH, KOH, LiOH, NaHCO₃, Na₂CO₃, K₂CO₃, organic    bases like tertiary alkyl amines and the like. Suitable solvents can    be selected from C₆-C₁₂ alcohols which may be linear or branched,    primary, secondary or tertiary alcohols such 1-hexanol, 2-hexanol,    3-hexanol, isohexanol, 1-heptanol, 2-heptanol, 3-heptanol,    4-heptanol, octanol, isooctanol, decanol, and the like or mixtures    thereof.

Alternatively, the processes [(i)-(vi)] described above can be repeatedby using the Clopidogrel base, Clopidogrel bisulfate and (S)-(+)Clopidogrel camphor-sulfonate prepared according to the improvedprocesses described by the applicant in U.S. Pat. No. 6,635,763.

The present invention also describes improved process for thepreparation of Form II of Clopidogrel bisulfate from the differentamorphous forms prepared according to any of the processes of thepresent invention. Form II is obtained by stirring the differentamorphous forms in solvents like, MTBE and the like or their mixtures.

The amorphous forms of (S)-(+)-Clopidogrel bisulfate includinghydrates/solvates (methanolates, ethanolates and the like), Form I andForm II of (S)-(+)-Clopidogrel bisulfate prepared according to theprocesses of the present invention may be characterized by their meltingpoint, physical characteristics, X-ray powder diffraction pattern, DSC,thermogravimetric analysis, differential scanning calorimetry, diffusedreflection IR absorption and/or by its solid state nuclear magneticresonance spectrum and % content of water, methanol, ethanol and othersolvates mentioned in processes described elsewhere in thespecification, including form stabilizers like various PEGs.

The advantages of the processes for preparation of different forms ofclopidogrel bisulfate according to the present

not hazardous as it does not use volatile chemicals like ethers.

scalable at plant level and so industrially useful

easy to operate

good recovery of solvents

gives high yield

The different forms of amorphous (S)-(+)-Clopidogrel bisulfatehydrates/solvates (methanolates, ethanolates and the like), Form I andForm II of (S)-(+)-Clopidogrel bisulfate prepared according to theprocesses of the present invention may be administered orally,parenterally or rectally without further formulation, or anypharmaceutically acceptable liquid carrier. The drug substance of thepresent invention may also be filled in a capsule directly for oraladministration. However, it is preferred that the drug substance isformulated with one or more excipients to prepare a pharmaceuticalcomposition, for example, an oral dosage form.

Another aspect of the present invention aims at providing the variouspharmaceutical compositions of the different amorphous forms of(S)-(+)-Clopidogrel bisulfate, Form I and Form II of (S)-(+)-Clopidogrelbisulfate prepared according to the present invention.

According to the present invention, the various amorphous forms of(S)-(+)-Clopidogrel bisulfate, Form I and Form II prepared according tothe processes of the present invention is formulated into pharmaceuticalcompositions for oral use containing required amount of the activeingredient per unit of dosage, in combination with at least onepharmaceutical excipient in the form of tablets, sugar coated tablets,capsules, injectable solutions, granules or a syrup. They can also beadministered rectally in the form of suppositories or can be parentallyadministered in the form of an injectable solution.

In another embodiment of the present invention a method of treatment anduse of the different amorphous forms of (S)-(+)-Clopidogrel bisulfate,Form I and Form II prepared according to the present invention, for thetreatment of cardiovascular disorders is provided, comprisingadministering, for example, orally or in any other suitable dosageforms, a composition of the invention in a therapeutically effectiveamount.

The following non-limiting examples illustrate the inventor's preferredmethods for preparing the amorphous forms as well as Form I & Form II of(S)-(+)-Clopidogrel bisulfate discussed in the invention and should notbe construed as limiting the scope of the invention in any way.

Example 1 Preparation of Clopidogrel Hydrogen Sulfate Hydrated AmorphousForm

Clopidogrel base (444.18 gms) was dissolved in methanol (4.136 L) withstirring at 25 to 30° C. Dilute sulfuric acid was added to the solutiondropwise in about 15 minutes of time at 5 to 10° C. The reaction mixturewas stirred for 30 minutes. Then the solvent was evaporated underreduced pressure at 50 to 55° C. Cyclohexane (2 L) was added to reactionmixture and the same was stirred, filtered and dried at 45 to 50° C. ina vacuum oven for 8 hours to obtain powder (493 gms, 85%) whosecharacterization data showed to be the hydrated amorphous form. KF valueis found in the range from 1 to 3% water (in different batches) andpowder XRD data indicated to be amorphous with no peaks due tocrystalline form.

Example 2 Preparation of Clopidogrel Hydrogen Sulfate Hydrated AmorphousForm

Clopidogrel base (500 gms) was dissolved in methanol (4.65 L) and water(65 ml) with stirring at 25 to 30° C. Concentrated sulfuric acid wasadded to the solution dropwise in about 15 minutes of time at 5 to 10°C. The reaction mixture was stirred for 30 minutes. Then the solvent wasevaporated under reduced pressure at 50 to 55° C. Cyclohexane (2 L) wasadded to the reaction mixture. The reaction mixture was stirred,filtered and dried at 45 to 50° C. in a vacuum oven for 8 hours toobtain powder (600 gms, 92%) whose characterization data showed to bethe hydrated amorphous form. KF value is found in the range from 1 to 3%(in different batches) and powder XRD data indicated to be amorphouswith no peaks due to crystalline form.

Example 3 Preparation of Clopidogrel Hydrogen Sulfate Hydrated AmorphousForm

Suspension of Clopidogrel hydrogen sulfate (50 gms) was stirred indichloromethane (300 ml) and subsequently basified by adding NaHCO₃solution (10%, 500 ml) in it. The mixture was stirred at 25 to 30° C.for about 10 minutes. The layers were separated and the aqueous layerwas extracted with dichloromethane (50 ml.) and washed with water (100ml.). It was then dried over Na₂SO₄ and the solvent was distilled off ona water bath at 50 to 55° C. to obtain Clopidogrel free base (39.5 gms).

The Clopidogrel base (38.3 gms) obtained above was dissolved in methanol(356 mL) and water (5 ml) at 25 to 30° C. Concentrated sulfuric acid wasadded to the solution dropwise in about 15 minutes of time at 5 to 10°C. The reaction mixture was stirred for 30 minutes. The solvent wasevaporated under reduced pressure at 50 to 55° C. Cyclohexane (175 mL)was added to the reaction mixture and stirred for approximately 10minutes and filtered, dried at temperature in the range from 45 to 50°C. in a vacuum oven for approximately 8 hours to obtain powder (46 gms,92%) whose characterization data showed to be the hydrated amorphousform a KF value is found in the range from 1 to 3% (in differentbatches) and powder XRD data indicated to be amorphous with no peaks dueto crystalline form.

Example 4 Preparation of Clopidogrel Hydrogen Sulfate Hydrated AmorphousForm

Suspension of Clopidogrel hydrogen sulfate (61 gms) was stirred indichloromethane (360 ml) and subsequently basified with NaHCO₃ solution(10%, 600 ml). The mixture was stirred at 25 to 30° C. for about 10minutes. The layers were separated and the aqueous layer was extractedwith dichloromethane (60 ml.) and washed with water (120 ml.). It wasthen dried over Na₂SO₄ and the solvent was distilled off on a water bathat a temperature in the range from 50 to 55° C. to obtain Clopidogrelfree base (46.0 gms)

Clopidogrel base (46 gms) obtained above was dissolved in methanol (427mL) at 25 to 30° C. Dilute sulfuric acid was added to the solutiondropwise in about 15 minutes at 5 to 10° C. The reaction mixture wasstirred for 30 minutes. The solvent was evaporated under reducedpressure at 50 to 55° C. Cyclohexane (190 mL) was added to the reactionmixture and stirred for approximately 10 minutes and filtered, and driedat temperature in the range from 45 to 50° C. in a vacuum oven forapproximately 8 hours to obtain powder (54 gms, 90%) whosecharacterization data showed to be the hydrated amorphous form. KF valueis found in the range from 1 to 3% (in different batches) and powder XRDdata indicated to be amorphous with no peaks due to crystalline form.

Example 5 Preparation of Clopidogrel Hydrogen Sulfate Hydrated AmorphousForm

A suspension of (S)-(+) Clopidogrel camphor sulphonate (66 gms) wasstirred in dichloromethane (300 ml) and subsequently basified withNaHCO₃ solution (10%, 500 ml). The mixture was stirred at 25 to 30° C.for about 10 minutes. The layers were separated and the aqueous layerwas extracted with dichloromethane (50 ml.) and washed with water (100ml.). It was then dried over Na₂SO₄ and the solvent was distilled off ona water bath at a temperature in the range from 50 to 55° C. to obtainClopidogrel free base (39.5 gms)

Clopidogrel base (38.3 gms) obtained above was dissolved in methanol(356 mL) at 25 to 30° C. Dilute sulfuric acid was added to the solutiondropwise in about 15 minutes of time at 5 to 10° C. The reaction mixturewas stirred for 30 minutes. Then the solvent was evaporated underreduced pressure at 50 to 55° C. Cyclohexane (175 mL) was added to thereaction mixture and stirred for approximately 10 minutes and filtered,dried at 45 to 50° C. in a vacuum oven for approximately 8 hours toobtain powder (46 gms, 92%) whose characterization data showed to be thehydrated amorphous form. KF value is found in the range from 1 to 3% (indifferent batches) and powder XRD data indicated to be amorphous with nopeaks due to crystalline form.

Example 6 Preparation of Clopidogrel Hydrogen Sulfate Hydrated AmorphousForm

A suspension of (S)-(+) Clopidogrel camphor sulphonate (132 gms) wasstirred in dichloromethane (600 ml) and subsequently basified withNaHCO₃ solution (10%, 1000 ml). The mixture was stirred at a temperaturein the range from 25 to 30° C. for about 10 minutes. The layers wereseparated and aqueous layer was extracted with dichloromethane (100 ml.)and washed with water (200 ml.). The organic layer was then dried overNa₂SO₄ and solvent was distilled off on a water bath at a temperature inthe range from 50 to 55° C. to obtain Clopidogrel free base (79 gms)

Clopidogrel base (76.6 gms) obtained above was dissolved in methanol(712 mL) and water (10 ml) at 25 to 30° C. Concentrated sulfuric acidwas added to the solution dropwise in about 15 minutes of time at 5 to10° C. The reaction mixture was stirred for 30 minutes. The solvent wasevaporated under reduced pressure at 50 to 55° C. Cyclohexane (350 mL)was added to the reaction mixture and stirred for approximately 10minutes, filtered and dried at 45 to 50° C. in a vacuum oven forapproximately 8 hours to obtain powder (90 gms, 90%) whosecharacterization data showed to be the hydrated amorphous form. KF valueis found in the range from 1 to 3% (in different batches) and powder XRDdata indicated to be amorphous with no peaks due to crystalline form.

Example 7 Preparation of Clopidogrel Hydrogen Sulfate Hydrated AmorphousForm

A suspension of (S)-(+) Clopidogrel hydrogen sulfate (110 gms) wasstirred in dichloromethane (1.1 L) The solution was stirred at 25 to 30°C. Water (132 ml) was added and the reaction mixture was stirred forapproximately 10 minutes. The reaction mixture was distilled atatmospheric pressure, on a water bath at a temperature in the range from50 to 55° C. and high vacuum was applied. Dichloromethane (500 ml) wasagain added to it, excess solvent was distilled off applying high vacuumat 50 to 55° C. The operation was repeated with 500 ml dichloromethane.Finally 250 ml dichloromethane was charged to the mixture andsubsequently the solvent was distilled off using high vacuum at atemperature 50 to 55° C., and a solid was obtained as a free flowingsolid. It was scratched and vacuum was reapplied for 10 to 15 minutes.Solid was transferred in to a drier in a dry area, dried at 50-53° C.for 8 hrs. to obtain powder (100 gms) whose characterization data showedto be the hydrated amorphous form.

Example 8 Preparation of Clopidogrel Hydrogen Sulfate Form I

Clopidogrel base (925 gms) was dissolved in n-hexanol (4.6 L) withstirring at 25 to 30° C. Dilute sulfuric acid was added to the reactionmixture at 10 to 15° C. The mixture was seeded with form-I crystal at 20to 25° C. The reaction mixture was stirred for approximately 8 to 10hours & subsequently further stirred for 8-10 hrs at 22 to 25° C. withlow agitation. The solid was then filtered and washed with methyl tertbutyl ether (1875 ml) and subsequently dried at 30 to 35° C. on a drier,to get 1095 g of clopidogrel bisulfate salt as crystals. Subsequentanalysis confirmed that the crystals were clopidogrel hydrogen sulfateForm-I.

Example 9 Preparation of Clopidogrel Hydrogen Sulfate Form I

Clopidogrel base (500 gms) was dissolved in n-hexanol (2.5 L) withstirring at 25 to 30° C. and water (10.3 ml) was added to it.Concentrated H₂SO₄ was added at 10-15° C. The reaction mixture wasseeded with form-I crystal at 20-25° C. The mixture was stirred at roomtemperature for 10-12 hrs and subsequently it was stirred at 22 to 25°C., for 1-2 hours with high agitation. The mixture was further stirredfor 5-8 hours at room temperature with low agitation. It was filtered,washed with methyl tert butyl ether (1500 ml) and dried at a temperaturein the range from 30 to 35° C. in a drier, to get 525 g of salt ascrystals. Subsequent analysis confirmed that the crystals wereclopidogrel hydrogen sulfate Form-I.

Example 10 Preparation of Clopidogrel Hydrogen Sulfate Form

Suspension of Clopidogrel hydrogen sulfate (660 gms) was stirred indichloromethane (3900 ml) & subsequently basified with NaHCO₃ solution(10%, 6500 ml). The reaction mixture was stirred at 25 to 30° C. forabout 10 minutes. The layers were separated and the aqueous layer wasextracted with dichloromethane (650 ml.) and washed with water (1300ml.). It was then dried over Na₂SO₄ and the solvent was distilled off ona water bath at 50 to 55° C. to obtain Clopidogrel free base (505 gms).

Clopidogrel base (500 gms) obtained above was dissolved in n-hexanol(2.5 L) with stirring at 25 to 30° C. and water (10.3 ml) was added toit. Concentrated sulfuric acid was added at 10 to 15° C. The reactionmixture was seeded with form-I crystals at a temperature in the rangefrom 20 to 25° C. The mixture was stirred at 25 to 30° C. for 10-12 hrs& subsequently it was stirred at high agitation, at a temperature in therange from 22 to 25° C. for 1-2 hrs. The reaction mixture was furtherstirred for 5-8 hrs at 22 to 25° C., at low agitation. The mixture wasthen filtered, washed with methyl tert butyl ether (1500 ml) and driedat 30-35° C. in a drier, to obtain 561 g clopidogrel bisulfate salt.Subsequent analysis confirmed that the crystals were clopidogrelhydrogen sulfate Form-I.

Example 11 Preparation of Clopidogrel Hydrogen Sulfate Form I

A suspension of Clopidogrel hydrogen sulfate (330 gms) was stirred indichloromethane (1950 ml) and subsequently with NaHCO₃ solution (10%,3300 ml). The mixture was stirred at 25 to 30° C. for about 10 minutes.The layers were separated and aqueous layer was extracted withdichloromethane (325 ml.) and washed with water (1300 ml,). It was thendried over Na₂SO₄ and the solvent was distilled off on a water bath at atemperature in the range from 50 to 55° C. to obtain Clopidogrel freebase (250 gms).

Clopidogrel base (250 gms) obtained above was dissolved in n-hexanol(1.25 L) with stirring at 25 to 30° C. Dilute sulfuric acid was added toit at 10 to 15° C. The reaction mixture was seeded with form-I crystalat 20 to 25° C. The mixture was stirred at room temperature, for 10-12hrs and subsequently it was stirred at 22 to 25° C., for 1-2 hours athigh agitation. The reaction mixture was further stirred for 5-8 hoursat room temperature at low agitation. The mixture was then filtered,washed with methyl tert butyl ether (750 ml) and dried at 30 to 35° C.in a drier, to get 260 g of salt as crystals. Subsequent analysisconfirmed that the crystals were clopidogrel hydrogen sulfate Form-I.

Example 12 Preparation of Clopidogrel Hydrogen Sulfate Form I

A suspension of (S)-(+) Clopidogrel camphor sulphonate (861.3 gms) wasstirred in dichloromethane (450 ml), and subsequently basified withNaHCO₃ solution (10%, 6500 ml). The mixture was stirred at 25 to 30° C.for about 10 minutes. The layers were separated and the aqueous layerwas extracted with dichloromethane (900 ml.) and washed with water (1800ml.). It was then dried over Na₂SO₄ and solvent was distilled off on awater bath at a temperature in the range from 50 to 55° C. to obtainClopidogrel free base (500 gms).

Clopidogrel base (500 gms) obtained above was dissolved in n-hexanol(2.5 L) with stirring at 25 to 30° C. and water (10.3 ml) was added toit. Concentrated sulfuric acid was added to it at 10 to 15° C. Thereaction mixture was seeded with form-I crystal at 20 to 25° C. Thereaction mixture was stirred at room temperature for 10-12 hrs andsubsequently it was stirred at 22 to 25° C., for 1-3 hours at highagitation. The reaction mixture was further stirred for 5-8 hours atroom temperature at low agitation. Then, the reaction mixture wasfiltered, washed with methyl tert butyl ether (1500 ml) and dried at 30to 35° C. in drier, to obtain 561 g of Clopidogrel bisulfate salt.Subsequent analysis confirmed that the crystals were clopidogrelhydrogen sulfate Form-I.

Example 13 Preparation of Clopidogrel Hydrogen Sulfate Form I

A suspension of (S)-(+) Clopidogrel camphor sulphonate (430.65 gms) wasstirred in dichloromethane (225 ml), and subsequently basified withNaHCO₃ solution (10%, 3250 ml). Stirred at 25 to 30° C. for about 10minutes. The layers were separated and the aqueous layer was extractedwith dichloromethane (450 ml.) and washed with water (900 ml.). It wasthen dried over Na₂SO₄ and distilled on a water bath at a temperature inthe range from 50 to 55° C. to obtain Clopidogrel free base (250 gms).

Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25 L) withstirring at 25 to 30° C. Dilute sulfuric acid was added at 10 to 15° C.The reaction mixture was seeded with form-I crystals at 20 to 25° C. Thereaction mixture was stirred at room temperature, for 10-12 hrs andsubsequently it was stirred at 22 to 25° C., for 1-3 hours at highagitation. The reaction mixture was further stirred for 5-8 hours at aroom temperature at low agitation. It was then filtered, washed withmethyl tert butyl ether (750 ml) and dried at 30 to 35° C. in a drier,to obtain 240 g of clopidogrel bisulfate salt. Subsequent analysisconfirmed that the crystals were clopidogrel hydrogen sulfate Form-I.

Example 14 Preparation of Clopidogrel Hydrogen Sulfate Form I

The amorphous form of Clopidogrel bisulfate (50 g) by any processmentioned above was dissolved in n-hexanol (250 mL) at 25 to 30° C. Thereaction mixture was stirred for 12 hours. The precipitated solid wasfiltered, washed with methyl tert butyl ether (50 ml), and dried at 30to 35° C. in a drier, to obtain 50 g of clopidogrel bisulfate salt.Subsequent analysis confirmed that the crystals were clopidogrelhydrogen sulfate Form-I.

Example 15 Preparation of Clopidogrel Hydrogen Sulfate Form I

A suspension of Clopidogrel hydrogen sulfate (330 gms) was stirred indichloromethane (1950 ml) and subsequently with NaHCO₃ solution (10%,3300 ml). The mixture was stirred at 25 to 30° C. for about 10 minutes.The organic layer was separated and aqueous layer was extracted withdichloromethane (325 ml.) and washed with water (1300 ml.). It was thendried over Na₂SO₄ and the solvent was distilled off on a water bath at atemperature in the range from 50 to 55° C. to obtain Clopidogrel freebase (250 gms).

Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25 L) withstirring at 25 to 30° C. Dilute sulfuric acid was added to it at 10 to15° C. The mixture was stirred at room temperature, for 6 hrs andsubsequently it was stirred at 22 to 25° C., for 5 hours at highagitation. The reaction mixture was further stirred for 4-5 hours atroom temperature at low agitation. The mixture was then filtered, washedwith methyl tert butyl ether (750 ml) and dried at 30 to 35° C. in adrier, to get 280 g of salt as crystals. Subsequent analysis confirmedthat the crystals were Clopidogrel hydrogen sulfate Form-I.

Example 16 Preparation of Clopidogrel Hydrogen Sulfate Form I

A suspension of Clopidogrel hydrogen sulfate (330 gms) was stirred indichloromethane (1950 ml) and subsequently basified with NaRCO₃ solution(10%, 3300 ml). The mixture was stirred at 25 to 30° C. for about 10minutes. The layers were separated and the aqueous layer was extractedwith dichloromethane (325 ml.) and washed with water (1300 ml.). It wasthen dried over Na₂SO₄ and distilled off on a water bath at atemperature in the range from 50 to 55° C. to obtain Clopidogrel freebase (250 gms).

Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25 L) withstirring at 25 to 30° C. and water (5 ml) was added to it. To themixture was added concentrated sulfuric acid at 10 to 15° C. The mixturewas stirred at room temperature for 6 hrs and subsequently it wasstirred at 22 to 25° C., for 5 hours at high agitation. The reactionmixture was further stirred for 4 hours at room temperature at lowagitation. The mixture was then filtered, washed with methyl tert butylether (750 ml) and dried at 30 to 35° C. in a drier, to get 270 g ofClopidogrel bisulfate salt as crystals. Subsequent analysis confirmedthat the crystals were Clopidogrel hydrogen sulfate Form-I.

Example 17 Preparation of Clopidogrel Hydrogen Sulfate Form I

A suspension of Clopidogrel camphor sulphonate (430.65 gms) was stirredin dichloromethane (225 ml), and subsequently basified with NaHCO₃solution (10%, 3300 ml). The mixture was stirred at 25 to 30° C. forabout 10 minutes. The layers were separated and the aqueous layer wasextracted with dichloromethane (450 ml.) and washed with water (900ml.). It was then dried over Na₂SO₄ and the solvent was distilled off ona water bath at a temperature in the range from 50 to 55° C. to obtainClopidogrel free base (250 gms).

Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25 L) withstirring at 25 to 30° C. Dilute sulfuric acid was added to it at 10 to15° C. The mixture was stirred at room temperature for 6 hrs andsubsequently it was stirred at 22 to 25° C., for 5 hours at highagitation. The reaction mixture was further stirred for 4 hours at roomtemperature at low agitation. The mixture was then filtered, washed withmethyl tert butyl ether (750 ml) and dried at 30 to 35° C. in a drier toget 250 g of Clopidogrel bisulfate salt as crystals. Subsequent analysisconfirmed that the crystals were Clopidogrel hydrogen sulfate Form-I.

Example 18 Preparation of Clopidogrel Hydrogen Sulfate Form I

A suspension of Clopidogrel camphor sulphonate (430.65 gms) was stirredin dichloromethane (225 ml), and subsequently basified with NaHCO₃solution (10%, 3300 ml). The reaction mixture was stirred at 25 to 30°C. for about 10 minutes. The layers were separated and the aqueous layerwas extracted with dichloromethane (450 ml.) and washed with water (900ml.). It was then dried over Na₂SO₄ and the solvent was distilled off ona water bath at a temperature in the range from 50 to 55° C. to obtainClopidogrel free base (250 gms).

Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25 L) withstirring at 25 to 30° C. and water (5 ml) was added followed by additionof concentrated sulfuric acid at 10 to 15° C. The mixture was stirred atroom temperature, for 6 hrs and subsequently it was stirred at 22 to 25°C., for 5 hours at high agitation. The reaction mixture was furtherstirred for 4 hours at room temperature at low agitation. The mixturewas then filtered, washed with methyl tent-butyl ether (750 ml) anddried at 30 to 35° C. in a drier, to get 280 g of Clopidogrel bisulfatesalt as crystals. Subsequent analysis confirmed that the crystals wereClopidogrel hydrogen sulfate Form-4.

Example 19 Preparation of Clopidogrel Hydrogen Sulfate Form I

Clopidogrel base (39 gms) was dissolved in n-heptanal (154 mL) withstirring at 25 to 30° C. and water (0.8 ml) was added to it.Concentrated H₂SO₄ was added at 10-15° C. The reaction mixture wasseeded with form-I crystal at 20-25° C. The reaction mixture was stirredat room temperature, for 21 hrs. It was filtered, washed with methyltert-butyl ether (50 ml) and dried at a temperature in the range from 30to 35° C. in a drier, to get 42 g of salt as crystals. Subsequentanalysis confirmed that the crystals were Clopidogrel hydrogen sulfateForm-I.

Example 20 Preparation of Clopidogrel Hydrogen Sulfate Form I

Clopidogrel base (50 gms) was dissolved in n-heptanol (154 mL) withstirring at 25 to 30° C. and dilute H₂SO₄ was added at 10-15° C. Thereaction mixture was seeded with form-I crystal at 20-25° T. Thereaction mixture was stirred at room temperature, for 20-24 hrs,filtered, washed with methyl tert-butyl ether (50 ml) and dried attemperature in the range from 30 to 35° C. in a drier, to get 50 g ofClopidogrel bisulfate salt as crystals. Subsequent analysis confirmedthat the crystals were Clopidogrel hydrogen sulfate Form-I.

Example 21 Preparation of Clopidogrel Hydrogen Sulfate Form I

Clopidogrel base (10 gms) was dissolved in decan-1-ol (50 mL) withstirring at 25 to 30° C. and water (0.2 ml) was added to it.Concentrated H₂SO₄ was added at 10-15° C. Solid material precipitated.The mixture was stirred at room temperature, for 24 hrs. It wasfiltered, washed with methyl tert-butyl ether (30 ml) and dried attemperature in the range from 30 to 35° C. in a drier, to get 7 g ofClopidogrel bisulfate salt as crystals. Subsequent analysis confirmedthat the crystals were clopidogrel hydrogen sulfate Form-I.

Example 22 Preparation of Clopidogrel Hydrogen Sulfate Form

Clopidogrel base (10 gms) was dissolved in decan-1-ol (50 mL) withstirring at 25 to 30° C. Dilute H₂SO₄ was added at 10-15° C. when thesolid material precipitated. The reaction mixture was stirred at roomtemperature, for 24 hrs. Then the mixture was filtered, washed withmethyl tert butyl ether (30 ml) and dried at a temperature in the rangefrom 30 to 35° C. in a drier, to get 8 g of Clopidogrel bisulfate saltas crystals. Subsequent analysis confirmed that the crystals were ofClopidogrel hydrogen sulfate Form-I.

Example 23 Preparation of Clopidogrel Hydrogen Sulfate Form II

The amorphous Clopidogrel bisulfate (50 g) was dissolved inmethyl-tert-butyl ether (500 mL) at 25 to 30° C. The reaction mixturewas stirred for 24 hours. Then the reaction mixture was filtered, washedwith methyl tert-butyl ether (50 ml), and dried at 30 to 35° C. in adrier, to obtain 49 g of clopidogrel bisulfate salt Form-II. Subsequentanalysis confirmed that the crystals were of Clopidogrel hydrogensulfate Form-II.

1. A process for the preparation of hydrated form ofamorphous(S)-(+)-Clopidogrel bisulfate comprising i. treatingClopidogrel base with dil. H₂SO₄ in one or more suitable solvent(s); ii.removing the solvent and isolating amorphous form by addition of one ormore suitable antisolvent(s).
 2. A process for the preparation ofhydrated form of amorphous(S)-(+)-Clopidogrel bisulfate comprising i.treating Clopidogrel base in one or more suitable solvent(s) and waterwith concentrated H₂SO₄; ii. removing the solvent and isolating theamorphous form by addition of one or more suitable antisolvent(s).
 3. Aprocess for the preparation of hydrated form ofamorphous(S)-(+)-Clopidogrel bisulfate comprising i. treatingClopidogrel bisulfate in dichloromethane-water with one or more suitablebase(s), to obtain Clopidogrel base; ii. treating the Clopidogrelbase(s) with dil. H₂SO₄ in one or more suitable solvent(s); iii. removalof the solvent(s) and isolating the amorphous form by addition ofsuitable one or more antisolvent(s).
 4. A process for the preparation ofhydrated form of amorphous(S)-(+)-Clopidogrel bisulfate comprising i.treating Clopidogrel bisulfate in dichloromethane-water with one or moresuitable base(s), to obtain Clopidogrel base; ii. treating Clopidogrelbase with concentrated H₂SO₄ in a mixture of suitable solvent(s) andwater, iii. removing the solvent and isolating the amorphous form byaddition of one or more suitable antisolvent(s).
 5. A process for thepreparation of hydrated form of amorphous (S)-(+)-Clopidogrel bisulfatecomprising i. treating (S)-(+) Clopidogrel camphor-sulfonate in one ormore suitable solvent(s) with a suitable base(s) to obtain Clopidogrelbase wherein the suitable solvent is selected from ethyl acetate,dichloromethane, dichloroethane, chloroform or mixtures thereof ii.treating the Clopidogrel base with concentrated H₂SO₄ in a mixture ofone or more suitable solvent(s) and water, iii. removing the solvent(s)and isolating the amorphous form by addition of suitable one or moreantisolvent(s).
 6. A process for the preparation of hydrated form ofamorphous(S)-(+)-Clopidogrel bisulfate comprising i. treating (S)-(+)Clopidogrel camphor-sulfonate in one or more suitable a solvent(s) withone or more suitable base(s), to obtain Clopidogrel base wherein thesuitable solvent is selected from ethyl acetate, dichloromethane,dichloroethane, chloroform, or mixture thereof; ii. treating theClopidogrel base with dilute H2SO4 in one or more suitable solvent(s);iii. removing the solvent and isolating the amorphous form by additionof one or more suitable antisolvent(s).
 7. A process as claimed claim 1,wherein the solvent is selected from the group consisting of methanol,ethanol, propanol, isopropanol, 1-butanol, 2-butanol, dichloromethane,dimethyl formamide, dimethyl acetamide, 1,4-dioxane, tetrahydrofuran,and mixtures thereof.
 8. A process as claimed in claim 1, wherein theantisolvent is selected from the group consisting of pentane, n-hexane,heptane, cyclohexane, pet ether, and mixtures thereof.
 9. A process asclaimed in claim 1, wherein the base is selected from the groupconsisting of NaOH, KOH, LiOH, NaHCO₃, Na₂CO₃, K₂CO₃, and tertiary alkylamines. 10-21. (canceled)
 22. A process for the preparation of form IIof (S)-(+)-Clopidogrel bisulfate comprising stirring the differentamorphous forms in Methyl-tert-butyl ether and subsequent removal of thesolvent.
 23. A method of treating cardiovascular and related diseases byproviding a patient in need thereof, the various forms of(S)-(+)-Clopidogrel bisulfate prepared according to the presentinvention or pharmaceutical compositions containing the same. 24.(canceled)